PA clan of proteases

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PA clan of
SCOP2
50494 / SCOPe / SUPFAM
Membranome319

The PA clan (

viruses.[2]

The common use of the catalytic triad for hydrolysis by multiple clans of proteases, including the PA clan, represents an example of convergent evolution.[7] The differences in the catalytic triad within the PA clan is also an example of divergent evolution of active sites in enzymes.[2]

History

In the 1960s, the

structural homology despite no discernible sequence similarity and even a different nucleophile.[2][10][11] Based on structural homology, a superfamily was defined and later named the PA clan (by the MEROPS classification system). As more structures are solved, more protease families have been added to the PA clan superfamily.[12][13]

Etymology

The P refers to Proteases of mixed nucleophile. The A indicates that it was the first such clan to be identified (there also exist the PB, PC, PD and PE clans).[1]

Structure

west nile virus protease (PDB: 1fp7​), exfoliatin toxin (PDB: 1exf​), HtrA protease (PDB: 1l1j​), snake venom plasminogen activator (PDB: 1bqy​), chloroplast protease (PDB: 4fln​) and equine arteritis virus protease (PDB: 1mbm
​).
DALI
b-factor putty (wider regions indicate greater flexibility) for the structure of TEV protease. Substrate in black, active site triad in red. The final 15 amino acids (222-236) of the enzyme C-terminus are not visible in the structure as they are too flexible. (PDB: 1lvm, 1lvb
​)

Despite retaining as little as 10% sequence identity, PA clan members isolated from viruses, prokaryotes and eukaryotes show

structural homology and can be aligned by structural similarity (e.g. with DALI).[3]

Double β-barrel

PA clan proteases all share a core motif of two

β-barrels with covalent catalysis performed by an acid-histidine-nucleophile catalytic triad motif. The barrels are arranged perpendicularly beside each other with hydrophobic residues holding them together as the core scaffold for the enzyme. The triad residues are split between the two barrels so that catalysis takes place at their interface.[14]

Viral protease loop

In addition to the double β-barrel core, some viral proteases (such as

specificity
.

Evolution and function

See also: Catalytic triad § Comparison of serine and cysteine hydrolase mechanisms

Catalytic activity

clan PA
, family C3).

exopeptidases.[17][18]

Biological role and substrate specificity

In addition to divergence in their core catalytic machinery, the PA clan proteases also show wide divergent evolution in function. Members of the PA clan can be found in

haemotoxin and interfere with the victim's blood clotting cascade. Additionally, bacteria such as Staphylococcus aureus secrete exfoliative toxin which digest and damage the host's tissues. Many viruses express their genome as a single, massive polyprotein and use a PA clan protease to cleave this into functional units (e.g. polio, norovirus, and TEV proteases).[19][20]

There are also several

pseudoenzymes in the superfamily, where the catalytic triad residues have been mutated and so function as binding proteins.[21] For example, the heparin-binding protein Azurocidin has a glycine in place of the nucleophile and a serine in place of the histidine.[22]

Families

Within the PA clan (P=proteases of mixed

serine proteases
). Despite the lack of sequence homology for the PA clan as a whole, individual families within it can be identified by sequence similarity.

Family Examples Known structure?
C03 polio-type picornain 3C (poliovirus) Yes
C04
tobacco etch virus protease (tobacco etch virus
) 		Yes
C24 rabbit hemorrhagic disease virus 3C-like peptidase (rabbit hemorrhagic disease virus) No
C30 porcine transmissible gastroenteritis virus-type main peptidase (transmissible gastroenteritis virus) Yes
C37 calicivirin (Southampton virus) Yes
C62 gill-associated virus 3C-like peptidase (
gill-associated virus
) 		No
C74 pestivirus NS2 peptidase (bovine viral diarrhea virus 1) No
C99 iflavirus processing peptidase (Ectropis obliqua picorna-like virus) No
C107 alphamesonivirus 3C-like peptidase (Cavally virus) No
S01
Bos taurus
) 		Yes
S03 togavirin (Sindbis virus) Yes
S06 IgA specific serine endopeptidase (Neisseria gonorrhoeae) Yes
S07
yellow fever virus
) 		No
S29 hepacivirin (hepatitis C virus) Yes
S30
plum pox virus
) 		No
S31 pestivirus NS3 polyprotein peptidase (bovine viral diarrhea virus 1) No
S32
equine arteritis virus
) 		Yes
S39 sobemovirus peptidase (cocksfoot mottle virus) Yes
S46 dipeptidyl-peptidase 7 (Porphyromonas gingivalis) No
S55 SpoIVB peptidase (Bacillus subtilis) No
S64 Ssy5 peptidase (Saccharomyces cerevisiae) No
S65 picornain-like cysteine peptidase (Breda-1 torovirus) No
S75 White bream virus serine peptidase (White bream virus) No

See also

References

  1. ^
    PMID 22086950
    .
  2. ^
    PMID 3186696
    .
  3. ^
    PMID 22624962
    .
  4. PMID 8844831
    .
  5. ^ "MEROPS - Archaeal S01 proteases".
  6. PMID 23689588
    .
  7. ^
    PMID 23382230
    .
  8. PMID 1142424
    .
  9. PMID 8642605
    .
  10. S2CID 23268152
    .
  11. ^
    PMID 12377789
    .
  12. S2CID 4312593
    .
  13. PMID 8617757
    .
  14. PMID 2475971
    .
  15. PMID 22624962
    .
  16. PMID 26097079
    .
  17. PMID 24598890
    .
  18. PMID 24827749
    .
  19. ISBN 9780123822192
    .
  20. S2CID 3343824
    .
  21. PMID 12377129
    .
  22. S2CID 19949043
    .

External links
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